Single-cell RNA sequencing reveals the adverse role of cDC3s in the response of ulcerative colitis patients to anti-TNF-α therapy.

BACKGROUND: Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease that belongs to the inflammatory bowel disease (IBD). The complex etiology of UC contributes to heterogeneous clinical outcomes in treatment. In clinical practice, approximately 30% of UC patients do not respond to first-line treatment with anti-TNF-α therapy. METHODS: In this study, we performed single-cell sequencing of intestinal mucosal tissue before (pre) and after (post) anti-TNF-α therapy in UC patients and analyzed it in relation to therapy response (-R) and non-response (-NR). RESULTS: We found that immune cell profiles differed between the pre-R and post-R groups. Specifically, the proportion of type 3 conventional dendritic cells (cDC3s) with distinct transcriptomes was lower in the post-R group than in the pre-R group and was not different between the pre-NR and post-NR groups. Cell trajectory analysis revealed that the number of cells differentiated into cDC3s significantly decreased in the post-R group, and the genes related to the MAPK signaling pathway obviously increased in these cells. Additionally, the interaction analysis of ligands and receptors revealed that the interactions between HLA-DPA1/DPB1 in fibroblasts and TNFSF9 in cDC3s and between CD44 in fibroblasts and TYROBP in cDC3s were significantly weakened in the post-R group compared to the pre-R group. CONCLUSION: We provide a comprehensive resource detailing the dynamic changes in immune cells during TNF-α therapy in UC patients and identify the reduction in the number of functionally distinct cDC3s as a potential biomarker for predicting anti-TNF-α therapy outcomes.